Helping Alzheimer’s Patients Bring Back Memories

People of all ages have moments when it feels like we’re on the edge of recalling something but can’t quite do it—where we parked our car or left our phone, for example, or what name goes with that familiar face. It’s extremely frustrating in the moment, but for most of us, we can usually remember if we try. For patients with Alzheimer’s, Huntington’s and many other dementia-causing diseases, however, memory loss is much more profound.

Given the steady rise in the numbers of Alzheimer’s patients, in particular, the research community and pharmaceutical companies agree that the development of treatment strategies is critical, now more than ever. Yet despite decades of research, we are still trying to understand why these patients can’t remember—and trying to find some way we might be able to help.

But we may be closer to an answer.

A well-known feature of early Alzheimer’s is a difficulty remembering recent events. We’ve always assumed that there are two possible explanations: one is that these patients can’t store new information properly in the brain; the other is that their ability to recall stored information has been weakened. But maybe there’s another way to think about it. Consider a public library in which each book represents a memory. If the library doesn’t have the book you want, you’re out of luck. This would be like asking Alzheimer’s patients to remember something that hasn’t been stored in their brain in the first place.

Even if the library has the book, though, you still need several pieces of information to locate it—what floor it’s on, what rack, what row on the rack. If you were missing some of that information, you wouldn’t find it either. That corresponds to the second assumption about why people with Alzheimer’s can’t remember. Although most research has focused on ways of improving memory storage in Alzheimer’s, this has not led to led to treatments capable of improving recall.

On the other hand, scientific evidence in support of the “weakened memory recall” idea in Alzheimer’s has been difficult to obtain, which is why this possibility has received considerably less attention. But in a Nature paper published in 2016, our team investigated both memory storage and memory recall processes in an animal model of early Alzheimer’s disease. In clinical research, there is no simple method to distinguish between memory storage versus recall deficits in Alzheimer’s patients, because standard cognitive tests rely on the patient’s ability to verbally describe previous events.

To circumvent this issue, I developed an approach that allowed us to activate the neurons that store memory information, referred to as memory engrams, through optogenetics—that is, introducing a gene that is light sensitive into the memory engram cells of “Alzheimer’s” mice, then delivering blue light pulses to activate them—and measuring memory recall strength directly. To our surprise, we found comparable numbers of engram cells in normal healthy animals and Alzheimer’s animals, suggesting that the initial memory storage process is intact. Targeting the recall process in Alzheimer’s animals led

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